The role of hypertension in cardiac dysfunction is continually evolving. Therefore, the treatment of hypertension continues to be clinically important. The discovery of new agents with fewer undesirable side effects is a therapeutic target since hypertension must be treated chronically. Long term toxicity as well as long term patient compliance are important considerations in the development of new antihypertensive agents.
One of the blood pressure regulating systems in man is the renin-angiotensin system. The renin-angiotensin system produces angiotensinogen in the kidney which is converted by renin to angiotensin I. The nonvasoconstricting peptide angiotensin I is converted by angiotensin convening enzyme (ACE) to angiotensin II, a potent vasoconstrictor. The discovery of nonpeptide angiotensin converting enzyme (ACE) inhibitors represented an important new step in the treatment of hypertension and several of these inhibitors, such as captopril and enalapril, are widely accepted. Progress toward renin inhibitors as therapeutic agents, however, has been far less successful.
Direct antagonism of angiotensin II binding at the receptor is an attractive goal because it is the actual vasoconstricting event in this pathway. By inhibiting the receptor, one would expect to have fewer side effects than by inhibiting earlier steps in the pathway. Also, by acting at the receptor, as opposed to one of the enzymes, large deposits of angiotensinogen and angiotensin I should not build up. In some systems, this build up can give rise to shunting mechanisms which can lead to other side effects.
Duncia et al. [J. Med. Chem., (1990), 33, 1312]Carini et al. [J. Med. Chem. (1990), 33, 1330], Johnson et al. [Drug News and Perspectives, (1990), 3, (6), 337], Chang et al. (EP 041,594 A) and Roberts et al. (G.B. 18402) all describe compounds which are inhibitors of angiotensin II.
A number of 3-thio-1,2,4-triazoles have been described in the literature [Beyer, H. et al., Ber. (1960) 637, 135; Kroger, C. et al., Ber (1961 ) 643, 121; and Kroger, C. et al., Ber. (1961 ) 643, 128; CA99 (21): 175676W; CA102(25): 216901S; CA84(5): 29998b; CA83(26): 20942u. None of these compounds, however, is dibenzylated. The compounds of the present invention are bisbiphenyl or phenylphthalamate substituted 3-mercapto-1,2,4-triazoles.